Hu Miao, Fok Benny S P, Wo Siu-Kwan, Lee Vincent H L, Zuo Zhong, Tomlinson Brian
Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.
School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong.
Clin Exp Pharmacol Physiol. 2016 Jan;43(1):34-40. doi: 10.1111/1440-1681.12490.
Ursodeoxycholic acid (UDCA), a natural, dihydroxy bile acid, promotes gallstone dissolution and has been attributed with several other beneficial effects. The farnesoid X receptor (FXR) may influence the pharmacokinetics of UDCA by modulating the expression of bile acid transporters. This exploratory study examined whether common functional polymorphisms in FXR and in bile acid transporter genes affect the pharmacokinetics of exogenous UDCA. Polymorphisms in genes for transporters involved in bile acid transport, solute carrier organic anion 1B1 (SLCO1B1) 388A>G and 521T>C, solute carrier 10A1 (SLC10A1) 800 C>T and ATP-binding cassette B11 (ABCB11) 1331T>C, and the FXR -1G>T polymorphism were genotyped in 26 male Chinese subjects who ingested single oral 500-mg doses of UDCA. Plasma concentrations of UDCA and its major conjugate metabolite glycoursodeoxycholic acid (GUDCA) were determined. The mean systemic exposure of UDCA was higher in the five subjects with one copy of the FXR -1G>T variant allele than in those homozygous for the wild-type allele (n = 21) (AUC0-24 h : 38.5 ± 28.2 vs. 20.9 ± 8.0 μg h/mL, P = 0.021), but this difference appeared mainly due to one outlier with the -1GT genotype and elevated baseline and post-treatment UDCA concentrations. After excluding the outlier, body weight was the only factor associated with plasma concentrations of UDCA and there were no significant associations with the other polymorphisms examined. None of the polymorphisms affected the pharmacokinetics of GUDCA. This study showed that the common polymorphisms in bile acid transporters had no significant effect on the pharmacokinetics of exogenous UDCA but an effect of the FXR polymorphism cannot be excluded.
熊去氧胆酸（UDCA）是一种天然的二羟基胆汁酸，可促进胆结石溶解，并具有其他多种有益作用。法尼酯X受体（FXR）可能通过调节胆汁酸转运蛋白的表达来影响UDCA的药代动力学。这项探索性研究考察了FXR和胆汁酸转运蛋白基因中的常见功能性多态性是否会影响外源性UDCA的药代动力学。对参与胆汁酸转运的转运蛋白基因多态性进行了基因分型，包括溶质载体有机阴离子转运体1B1（SLCO1B1）388A>G和521T>C、溶质载体10A1（SLC10A1）800C>T以及ATP结合盒转运体B11（ABCB11）1331T>C，同时对26名口服单次500mg剂量UDCA的中国男性受试者进行了FXR -1G>T多态性基因分型。测定了血浆中UDCA及其主要共轭代谢产物甘氨熊去氧胆酸（GUDCA）的浓度。携带一份FXR -1G>T变异等位基因的5名受试者的UDCA平均全身暴露量高于野生型等位基因纯合子受试者（n = 21）（AUC0 - 24h：38.5±28.2 vs. 20.9±8.0μg h/mL，P = 0.021），但这种差异似乎主要是由于一名-1GT基因型的异常值以及基线和治疗后UDCA浓度升高所致。排除该异常值后，体重是与UDCA血浆浓度相关的唯一因素，与所检测的其他多态性无显著关联。所有多态性均未影响GUDCA的药代动力学。该研究表明，胆汁酸转运蛋白中的常见多态性对外源性UDCA的药代动力学无显著影响，但不能排除FXR多态性的影响。
